Besides exposing our general vulnerability to bioterrorism, the anthrax attacks of the fall of 2001 alerted the nation to the need to develop therapies and vaccines against Bacillus anthracis. B. anthracis produces two major virulence factors--an antiphagocytic poly-D-glutamic acid capsule and a tripartite toxin. Injection of the purified toxin causes rapid death of sensitive rodents and non-human primates, and immunization against the toxin protects against infection. Thus it is generally believed that death from anthrax infections results from the effects of the toxin. As a step towards developing new therapeutic interventions for anthrax, we propose to use a high-throughput screen to identify low molecular mass compounds that inhibit the action of anthrax toxin at the cellular level. We have developed a sensitive assay based on the effect of this toxin on mouse macrophages. Building on the experience of the Collier laboratory in studying anthrax toxin, we will characterize the most promising inhibitors found, to determine the specific step in toxin action that each inhibits. Lead compounds with low toxicity will be considered for testing in animal models of toxin action.